Howard Trachtman1, Peter Nelson2, Sharon Adler3, Kirk N Campbell4, Abanti Chaudhuri5, Vimal Kumar Derebail6, Giovanni Gambaro7, Loreto Gesualdo8, Debbie S Gipson9, Jonathan Hogan10, Kenneth Lieberman11,12, Brad Marder13, Kevin Edward Meyers14,15, Esmat Mustafa16, Jai Radhakrishnan17, Tarak Srivastava18,19, Miganush Stepanians20, Vladimír Tesar21,22, Olga Zhdanova23, Radko Komers24. 1. Division of Pediatric Nephrology, Department of Pediatrics, New York University School of Medicine, Langone Medical Center, New York, New York; howard.trachtman@nyumc.org radko.komers@retrophin.com. 2. Division of Nephrology and Kidney Research Institute, University of Washington, Seattle, Washington. 3. Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center, Torrance, California. 4. Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York. 5. Division of Pediatric Nephrology, Stanford University, Palo Alto, California. 6. Division of Nephrology and Hypertension, University of North Carolina Kidney Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 7. Division of Nephrology and Dialysis, Università Cattolica del Sacro Cuore, Fondazione Policlinico A. Gemelli, Rome, Italy. 8. Nephrology Unit, Department of Emergency and Organ Transplantation (DETO), Azienda Ospedaliero Universitaria Policlinico di Bari, Bari, Italy. 9. Division of Pediatric Nephrology, University of Michigan, Ann Arbor, Michigan. 10. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 11. Department of Pediatric Nephrology, Joseph M. Sanzari Children's Hospital, Hackensack University Medical Center, Hackensack, New Jersey. 12. Seton Hall-Hackensack Meridian School of Medicine, Hackensack, New Jersey. 13. Division of Transplant Research, Colorado Kidney Care, Denver, Colorado. 14. Division of Nephrology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 15. Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 16. Department of Nephrology and Research Division, Arizona Kidney Disease and Hypertension Center, Phoenix, Arizona. 17. Division of Nephrology, Columbia University, New York, New York. 18. Children's Mercy Hospital, Kansas City, Missouri. 19. University of Missouri School of Medicine, Kansas City, Missouri. 20. PROMETRIKA, LLC., Cambridge, Massachusetts. 21. Department of Nephrology, Charles University, Prague, Czech Republic. 22. General University Hospital, Prague, Czech Republic. 23. Division of Nephrology, New York University School of Medicine, New York, New York; and. 24. Department of Research & Development, Retrophin, Inc., San Diego, California howard.trachtman@nyumc.org radko.komers@retrophin.com.
Abstract
BACKGROUND: We evaluated and compared the effects of sparsentan, a dual endothelin type A (ETA) and angiotensin II type 1 receptor antagonist, with those of the angiotensin II type 1 receptor antagonist irbesartan in patients with primary FSGS. METHODS: In this phase 2, randomized, double-blind, active-control Efficacy and Safety of Sparsentan (RE-021), a Dual Endothelin Receptor and Angiotensin Receptor Blocker, in Patients with Focal Segmental Glomerulosclerosis (FSGS): A Randomized, Double-blind, Active-Control, Dose-Escalation Study (DUET), patients aged 8-75 years with biopsy-proven FSGS, eGFR>30 ml/min per 1.73 m2, and urinary protein-to-creatinine ratio (UP/C) ≥1.0 g/g received sparsentan (200, 400, or 800 mg/d) or irbesartan (300 mg/d) for 8 weeks, followed by open-label sparsentan only. End points at week 8 were reduction from baseline in UP/C (primary) and proportion of patients achieving FSGS partial remission end point (FPRE) (UP/C: ≤1.5 g/g and >40% reduction [secondary]). RESULTS: Of 109 patients randomized, 96 received study drugs and had baseline and week 8 UP/C measurements. Sparsentan-treated patients had greater reductions in UP/C than irbesartan-treated patients did when all doses (45% versus 19%; P=0.006) or the 400 and 800 mg doses (47% versus 19%; P=0.01) were pooled for analysis. The FSGS partial remission end point was achieved in 28% of sparsentan-treated and 9% of irbesartan-treated patients (P=0.04). After 8 weeks of treatment, BP was reduced with sparsentan but not irbesartan, and eGFR was stable with both treatments. Overall, the incidence of adverse events was similar between groups. Hypotension and edema were more common among sparsentan-treated patients but did not result in study withdrawals. CONCLUSIONS:Patients with FSGS achieved significantly greater reductions in proteinuria after 8 weeks of sparsentan versus irbesartan. Sparsentan was safe and well tolerated.
RCT Entities:
BACKGROUND: We evaluated and compared the effects of sparsentan, a dual endothelin type A (ETA) and angiotensin II type 1 receptor antagonist, with those of the angiotensin II type 1 receptor antagonist irbesartan in patients with primary FSGS. METHODS: In this phase 2, randomized, double-blind, active-control Efficacy and Safety of Sparsentan (RE-021), a Dual Endothelin Receptor and Angiotensin Receptor Blocker, in Patients with Focal Segmental Glomerulosclerosis (FSGS): A Randomized, Double-blind, Active-Control, Dose-Escalation Study (DUET), patients aged 8-75 years with biopsy-proven FSGS, eGFR>30 ml/min per 1.73 m2, and urinary protein-to-creatinine ratio (UP/C) ≥1.0 g/g received sparsentan (200, 400, or 800 mg/d) or irbesartan (300 mg/d) for 8 weeks, followed by open-label sparsentan only. End points at week 8 were reduction from baseline in UP/C (primary) and proportion of patients achieving FSGS partial remission end point (FPRE) (UP/C: ≤1.5 g/g and >40% reduction [secondary]). RESULTS: Of 109 patients randomized, 96 received study drugs and had baseline and week 8 UP/C measurements. Sparsentan-treated patients had greater reductions in UP/C than irbesartan-treated patients did when all doses (45% versus 19%; P=0.006) or the 400 and 800 mg doses (47% versus 19%; P=0.01) were pooled for analysis. The FSGS partial remission end point was achieved in 28% of sparsentan-treated and 9% of irbesartan-treated patients (P=0.04). After 8 weeks of treatment, BP was reduced with sparsentan but not irbesartan, and eGFR was stable with both treatments. Overall, the incidence of adverse events was similar between groups. Hypotension and edema were more common among sparsentan-treated patients but did not result in study withdrawals. CONCLUSIONS:Patients with FSGS achieved significantly greater reductions in proteinuria after 8 weeks of sparsentan versus irbesartan. Sparsentan was safe and well tolerated.
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